purpose of cross presentation

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Review Article
Published: 01 November 2001

Cross-presentation in viral immunity and self-tolerance

William R. Heath 1 &
Francis R. Carbone 2

Nature Reviews Immunology volume 1 , pages 126–134 ( 2001 ) Cite this article

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T lymphocytes can be separated into two subpopulations, based on their expression of CD4 and CD8. The CD4 + subset is primarily responsible for providing help to other immune cells, whereas CD8 + T cells are best known for their capacity to kill virus-infected cells.

Cross-presentation is defined as the processing of exogenous antigens into the major histocompatibility complex (MHC) class I pathway. Cross-priming and cross-tolerance refer to the induction of cytotoxic T lymphocyte (CTL) immunity or tolerance, respectively, that is induced by cross-presented antigens.

Despite the discovery of cross-priming in the mid-1970s, the antigen-presenting cell responsible for this process has only recently been identified. Bevan and co-workers provided evidence that it is the CD8 + dendritic cell (DC).

Although there are several pathways for cross-presentation, our current understanding of which pathway(s) operate in vivo for cross-presentation of cell-associated antigens that are derived from virus-infected cells or self tissues is minimal.

As well as providing a mechanism for generating immunity to intracellular infections, cross-presentation has been reported to participate in tolerance induction. Such cross-tolerance is most probably mediated by DCs and leads to the deletion of self-reactive CTLs.

Antigen expression levels, the site of expression, the time of expression and the availability of help, crucially determine whether self-antigens cause cross-tolerance.

There are few studies that unequivocally show cross-priming to be crucial for natural, protective, CTL immunity. This does not mean that cross-priming has no role in natural immunity, only that it remains difficult to discriminate between the role of cross-presentation and direct presentation in natural CTL priming.

Virus-specific CTL immunity has been shown to depend on bone marrow-derived cells (presumably DCs) for several infections, including influenza virus, vaccinia virus, poliovirus and lymphocytic choriomeningitis virus, consistent with a role for cross-priming in viral immunity.

One can envisage that cross-priming has an important role in cases where a virus infection is localized to a peripheral non-lymphoid compartment, such as for papilloma virus infection of the epithelial cells of the skin. In addition, cross-priming could be important where viruses have evolved mechanisms that specifically disrupt the immune functions of DCs.

T lymphocytes recognize peptide antigens presented by class I and class II molecules encoded by the major histocompatibility complex (MHC). Classical antigen-presentation studies showed that MHC class I molecules present peptides derived from proteins synthesized within the cell, whereas MHC class II molecules present exogenous proteins captured from the environment. Emerging evidence indicates, however, that dendritic cells have a specialized capacity to process exogenous antigens into the MHC class I pathway. This function, known as cross-presentation, provides the immune system with an important mechanism for generating immunity to viruses and tolerance to self.

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Acknowledgements

The authors thank several people for their suggestions upon reading drafts of this manuscript, including Dr G. Davey, Dr G. Belz, Dr J. Villadangos, Dr. G. Behrens, Ms J. Mintern, Ms M. Li and Dr M. Bevan.

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Francis R. Carbone

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Heath, W., Carbone, F. Cross-presentation in viral immunity and self-tolerance. Nat Rev Immunol 1 , 126–134 (2001). https://doi.org/10.1038/35100512

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REVIEW article

Current concepts of antigen cross-presentation.

$\r\nMaria Embgenbroich$

Life and Medical Sciences (LIMES) Institute, University of Bonn, Bonn, Germany

Dendritic cells have the ability to efficiently present internalized antigens on major histocompatibility complex (MHC) I molecules. This process is termed cross-presentation and is important role in the generation of an immune response against viruses and tumors, after vaccinations or in the induction of immune tolerance. The molecular mechanisms enabling cross-presentation have been topic of intense debate since many years. However, a clear view on these mechanisms remains difficult, partially due to important remaining questions, controversial results and discussions. Here, we give an overview of the current concepts of antigen cross-presentation and focus on a description of the major cross-presentation pathways, the role of retarded antigen degradation for efficient cross-presentation, the dislocation of antigens from endosomal compartment into the cytosol, the reverse transport of proteasome-derived peptides for loading on MHC I and the translocation of the cross-presentation machinery from the ER to endosomes. We try to highlight recent advances, discuss some of the controversial data and point out some of the major open questions in the field.

Introduction

Dendritic cells (DCs) scan the peripheral tissue for antigens. Upon their recognition, antigens are internalized and the DCs activated and migrate toward the draining lymph node, where they can induce an adaptive immune response ( 1 ). In order to do so, they need to process the internalized antigens and load antigen-derived peptides on major histocompatibility complex (MHC) molecules. Peptides loaded onto MHC II molecules can be recognized by antigen-specific CD4 + T helper cells. Similarly, peptides loaded on MHC I molecules can be recognized by antigen-specific CD8 + T cells, leading to their proliferation and the activation of their cytotoxic capacities.

The presentation of internalized antigens on MHC I molecules is a process termed cross-presentation. Efficient cross-presentation has been shown to be crucial in, e.g., the induction of an adaptive immune response against tumors and viruses that do not infect DCs directly and in the induction of peripheral tolerance ( 2 – 5 ).

The molecular mechanisms that regulate classical antigen presentation on MHC II molecules and cross-presentation, however, have been shown to be quite divers. For MHC II-restricted presentation, internalized antigens are degraded in endo/lysosomal compartments by proteases such as cathepsins. Newly synthesized MHC II molecules, which are stabilized by binding to the invariant chain (Ii), are transported from the ER toward this compartment, where Ii is degraded by lysosomal proteases, resulting in the binding of only a small peptide fragment (CLIP) to MHC II. Subsequently, CLIP is replaced by antigen-derived peptides by the chaperon HLA-DM ( 6 ).

In contrast to MHC II-restricted presentation, the molecular mechanisms regulating cross-presentation are less understood and in part discussed controversially. There seems to be a whole variety of pathways leading to antigen cross-presentation and, despite intensive investigations, the molecular mechanisms and individual contribution of each pathway are rather unclear.

In this review, we try to describe some of the recent advances in cross-presentation, focusing on the major cross-presentation pathways and highlighting some of the controversial observations in the field.

Cross-Presenting DC Subsets

Although many cells are able to present extracellular antigens on MHC I, DCs are considered to be the most prominent and most relevant cross-presenting cells.

In general, DCs are subdivided into conventional DCs (cDCs) and plasmacytoid DCs (pDCs). cDCs are further classified into cDC1 and cDC2 ( 7 ). In mice and human, cDC1 are characterized by the expression of the chemokine receptor XCR1 ( 7 – 9 ) and their development relies on the expression of the transcription factors IRF8 and Batf3 ( 10 – 12 ), whereas the development of cDC2 is mainly regulated by IRF4 ( 7 , 13 ). Additionally, murine cDC1 express either CD8 (in lymphoid tissues) or CD103 (in non-lymphoid tissues), whereas human cDC1 are characterized by the expression of BDCA-3 (CD141) ( 8 , 14 – 17 ).

The cDC1 are generally considered to be potent cross-presenting DCs in vivo . Accordingly, in murine lymphoid tissue, soluble and cell-associated OVA are cross-presented by resident CD8 + DCs ( 18 – 20 ), whereas soluble and cell-associated antigens in lung ( 21 , 22 ), intestine, and skin ( 23 – 25 ) are cross-presented by migratory CD103 + DCs. Further functional properties of cDC1 are the uptake of apoptotic cells via Clec9A/DNGR1 ( 26 – 29 ) and the responsiveness to TLR3 stimulation ( 30 ).

cDC1 express high levels of MHC I pathway genes ( 31 ), show high intra-endosomal reactive oxygen species (ROS) production and low acidification in endosomes ( 32 , 33 ), all features of efficient cross-presentation (see below). They express the small GTPase Rac2, which enables the assembly of the NAPDH oxidase complex NADPH oxidase 2 (NOX2), resulting in enhanced ROS production and active alkalization of endosomes ( 33 ). Additionally, cDC1 show only marginal expression levels of the C-type lectin Siglec-G, a potent inhibitor of NOX2 ( 34 ).

However, the cDC1 are not the only cross-presenting DC population. Many other DC subpopulations, including cDC2, have been shown to cross-present as well ( 35 – 39 ). For human DCs, it even has been demonstrated that BDCA3 + (cDC1s), BDCA1 + (cDC2s), and even pDCs all bear intrinsic capacities to cross-present extracellular antigens ( 40 ). The exact role of different cDC1 and cDC2 subpopulations in cross-presentation is, therefore, under debate and, especially since functional data on the physiological role of human DC subsets in cross-presentation is hard to obtain, future experiments will have to shed light on this question.

Although pDCs have been shown to be able to cross-present antigens ( 41 ), their role in cross-presentation in vivo is questionable, especially since their depletion did not affect cross-presentation and clearance of viral antigens ( 42 ).

Major Pathways of Antigen Cross-Presentation

Intensive research has clearly shown that there are a wide variety of mechanisms by which peptides derived from extracellular antigens can be presented on MHC I molecules. In general, there are two main cross-presentation pathways: the vacuolar pathway and the endosome-to-cytosol pathway (Figure 1 ). In the vacuolar pathway, antigen processing and loading onto MHC I molecules occurs within the endo/lysosomal compartment. After internalization, antigens are degraded by lysosomal proteases and antigen-derived peptides are loaded onto MHC class I molecules there. The lysosomal protease Cathepsin S has been demonstrated to play a crucial role in antigen degradation for the vacuolar pathway ( 43 ). In the endosome-to-cytosol pathway, internalized antigens need to be transported from the endosomal compartment into the cytosol, where they are degraded by the proteasome ( 44 – 46 ). Derived peptides are subsequently transported by the transporter associated with antigen processing (TAP) into the ER or back into the antigen-containing endosomes, where they can be loaded onto MHC class I ( 44 , 45 , 47 – 49 ). Although substantial evidence points out that some antigens indeed can be cross-presented independent of proteasomal degradation and TAP-mediated peptide transport by the vacuolar pathway ( 43 , 50 – 53 ), most cross-presentation studies report of cross-presentation via the endosome-to-cytosol pathway. The dependency of cross-presentation on proteasomal degradation seems logical, since the functional outcome of cross-presentation is the activation of antigen-specific cytotoxic T cells. After migration toward to site of infection, these T cells are fully equipped to kill potential target cells, like virus-infected cells or tumor cells. In order to become functionally active, T cells must recognize the same epitope presented on MHC I by the target cells. Importantly, MHC I-loaded peptides on target cells do not emerge from cross-presentation but rather are the result of direct (classical) MHC I-restricted presentation of endogenous antigens, in which peptides are generated by the proteasome. Since it is hard to assume that for all antigens, the proteasome and lysosomal proteases generate exactly the same epitopes, the dependency of cross-presentation on proteasomal degradation for at least a substantial part of the antigens might circumvent this problem. Accordingly, DCs deficient in the LMP7 subunit of the immunoproteasome are impaired in cross-presentation in vitro and in vivo ( 46 ). However, it needs to be mentioned that very few information about the in vivo significance of the vacuolar vs. endosome-to-cytosol pathway is available, pointing out that future experiments are needed to further investigate the relative importance of both pathways in vivo .

Figure 1 . Schematic overview of cross-presentation pathways. Internalized antigens can be presented via the vacuolar pathway or via the endosome-to-cytosol pathway. In the vacuolar pathway, antigens are degraded in endosomes by Cathepsin S and loaded onto major histocompatibility complex (MHC) I there. In the endosome-to-cytosol pathway, antigens are transported into the cytosol for proteasomal degradation. Afterward, antigen-derived peptides are transported back into the endosomes (soluble and particular antigens) or into the ER (particular antigens) via TAP. There, they are trimmed by IRAP (endosomes) or ERAP (ER) and loaded onto MHC I. They cross-presentation machinery might be translocated toward endosomes via Sec22b.

Delayed Antigen Degradation and its Role in Cross-Presentation

Over the last years, it has become clear that intra-endosomal antigen stability critically regulates cross-presentation, which efficiency is negatively affected by rapid lysosomal degradation of internalized antigens ( 54 ). Lysosomal maturation and activation of lysosomal proteases is fine-tuned by the transcription factor TFEB, an important regulator of cross-presentation ( 55 ).

It is generally assumed that rapid antigen degradation quickly destroys a large amount of epitopes before they can be processed properly and loaded onto MHC I molecules ( 56 , 57 ). Additionally, peptide-loaded MHC I molecules have a limited life span at the cell membrane ( 58 – 60 ). In order to enable T cell activation after migration toward the draining lymph node, however, prolonged cross-presentation seems to be essential. Therefore, limited antigen degradation in antigen-presenting cells might be a mechanism to generate a kind of intracellular antigen depot, from where continuous antigen processing and presentation might ensure the presence of peptide-loaded MHC I molecules over a longer period of time ( 61 ). Such intracellular antigen storage depots have also been shown in human monocytes, which accumulate long-peptide antigens for over 5 days in non-lysosomal compartments, where day are protected from rapid degradation ( 62 ).

Since DCs are the most efficient cross-presenting cells, these cells possess several mechanisms by which they can actively prevent rapid lysosomal antigen degradation.

First, it was demonstrated that DCs express lower levels of lysosomal proteases ( 63 ) and display a reduced velocity of endosome maturation ( 64 ) compared to other immune cells. Expression of asparagine endopeptidase and Cathepsins L, S, D, and B in phagosomes of DCs was clearly reduced compared to macrophages, resulting in impaired phagolysosomal degradation and prolonged antigen stability after internalization by DCs ( 63 ). The delivery of lysosomal proteases toward phagosomes was even further reduced after stimulation of DCs with LPS ( 64 ).

Second, in DCs, an active alkalization of endosomes prevents pH-dependent activation of lysosomal proteases. During lysosome maturation, protons are transported into the luminal space by the V-ATPase, leading to the activation of pH-dependent lysosomal proteases. Reduced V-ATPase activity in DCs might contribute to prevent a rapid drop in pH after antigen internalization ( 65 ). Additionally, DCs seem to have the unique capacity to alkalize their endosomes by the recruitment the NOX2 toward the endosomal membrane ( 32 , 66 ). There, NOX2 can mediate the generation of ROS, which in turn capture protons to build hydrogen peroxide (Figure 1 ). Proton trapping by ROS causes an active alkalization, impairing pH-dependent activation of lysosomal proteases, which in turn prevents rapid antigen degradation and stimulates cross-presentation ( 32 ). The recruitment of NOX2 toward endosomes is mediated by Rab27a ( 67 ).

Third, DCs express endocytosis receptors that specifically target non-degradative endosomal compartments. Previous studies have demonstrated that the endocytosis receptor used to internalize an antigen critically determines its intracellular routing and degradation ( 68 ). A previous study from our group demonstrated that antigens internalized by fluid phase pinocytosis or scavenger receptor-mediated endocytosis are rapidly targeted toward lysosomes, where they are efficiently degraded by lysosomal proteases, resulting in poor cross-presentation ( 68 ). However, if the same DCs simultaneously internalized the same antigen by the mannose receptor, it was targeted toward a distinct pool of early endosomes, which did not undergo rapid fusion with lysosomes and in which antigens were protected from lysosomal degradation, resulting in efficient cross-presentation of MR-internalized antigens ( 68 ). Although the role of the MR in in vivo cross-presentation has been discussed controversially ( 69 , 70 ), it now is clear that CD103 + DCs in liver and lung use this receptor for cross-presentation of, e.g., viral antigens ( 71 ). A correlation between antigen targeting into early endosomes clearly distinct from lysosomes and cross-presentation efficiency has also been confirmed in human DCs. Also in these cells, MR-mediated internalization resulted in its routing into early endosomes, retarded degradation and efficient cross-presentation, whereas uptake by DEC205 lead to antigen targeting into lysosomes, rapid lysosomal degradation, and hence poor cross-presentation ( 56 ). Interestingly, attenuating lysosomal degradation was sufficient to rescue the cross-presentation of DEC-205-internalized antigens ( 56 ), highlighting again the importance of intra-endosomal antigen stability for efficient cross-presentation. Additionally, the targeted region of the endocytosis receptor might also play a role in antigen degradation and presentation, adding even an additional degree of complexity. Figdor and colleagues demonstrated that antigen targeting toward the carbohydrate recognition domain of DC-SIGN delivers antigens to lysosomal compartments, resulting in rapid degradation and poor cross-presentation, whereas targeting the neck region of DC-SIGN causes antigen delivery in early endosomal compartments clearly distinct from lysosomes, causing prolonged stability and efficient cross-presentation ( 72 , 73 ).

Antigen Translocation into the Cytosol as Critical Step in Antigen Cross-Presentation

After being internalized into a non-degradative endosomal compartment, antigens need to be processed before they can be loaded onto MHC I. In the endosome-to-cytosol pathway, internalized antigens, therefore, need to be transported across the endosomal membrane into the cytosol for proteasomal degradation. Although this is a key step in antigen cross-presentation and significant efforts have been made to shed light on this process, the underlying mechanisms mediating such intracellular antigen transport are still topic of debate.

In general, if DCs enable access of endosomal antigens to the cytosol, this must be a process, which is controlled very tightly. Uncontrolled lysosome leakage would lead to the cytosolic release of Cathepsins, which in turn would activate the NLRP3 inflammasome ( 74 ) and result in pyroptosis, an inflammatory form of cell death ( 75 ). To avoid this, total lysosomal content cannot just be released into the cytosol in an uncontrolled fashion. Accordingly, antigens need to be unfolded ( 76 ) and disulfide bridges need to be reduced by the γ-interferon-inducible lysosomal thiol reductase GILT ( 77 ) before efficient translocation and hence cross-presentation can take place. This supports the idea that antigen translocation is highly regulated, might involve dislocation through a transmembrane pore complex, and is presumably not the result of simple lysosome leakage.

It is generally assumed that members of the ER-associated degradation (ERAD) machinery contribute in enabling antigen dislocation for cross-presentation. First indirect indications for a role of ERAD in this process came from observations describing the presence of ERAD components in the phagosomal membrane ( 47 , 48 ) and from experiments using the ERAD inhibitor Exotoxin A, which specifically represses cross-presentation ( 49 , 78 ).

First direct evidence for the involvement of the ERAD machinery came from the Cresswell group, who demonstrated an important role of the AAA ATPase p97 in antigen dislocation ( 49 ). Whereas expression of a dominant-negative p97 mutant in DCs represses cross-presentation, the addition of purified wild-type p97 but not the dominant-negative mutant to purified phagosomes enhanced antigen translocation ( 49 , 79 – 81 ), indicating that p97 indeed might provide the energy to pull endosomal antigens into the cytosol.

The identification of a dedicated translocon, which actually functions as a transmembrane pore complex to enable antigen dislocation across the endosomal membrane, has been (and still is) by far more difficult. One putative candidate, which has been proposed to mediate antigen dislocation into the cytosol over a decade ago, is the ERAD member Sec61 ( 49 , 78 ), a trimeric protein whose downregulation has been shown to inhibit antigen translocation and cross-presentation ( 79 , 82 ). However, since Sec61 plays an important role in the dislocation of proteins at the ER membrane, like, e.g., the dislocation of MHC I molecules themselves ( 83 ), it is very hard to distinguish endosome-specific effects of Sec61 from general effects at the ER. In an attempt to solve this problem, we generated Sec61-specific intracellular antibody (intrabody), which we fused to an ER retention signal ( 84 ), leading to the trapping of Sec61 in the ER and preventing its transport toward endosomes ( 82 ). By this means, we could demonstrate that the transport of Sec61 toward endosomes indeed is essential for antigen dislocation and cross-presentation. Additionally, we could demonstrate that the expression of the intrabody did not alter overall Sec61 expression and did not affected the ERAD-mediated dislocation of MHC I, TCR, CD3δ and the split venus protein at the ER membrane. This points out that ERAD activity at the ER remained unaltered by the expression of the intrabody. These data suggest that Sec61 indeed might serve as a translocon for cross-presentation (Figure 1 ). However, it cannot be formally excluded that the translation of another pore complex at the ER membrane is changed by manipulating intracellular Sec61 transport or that another putative pore complex is translocated toward endosomes in a complex with Sec61, being influences by intrabody expression. Additionally, Grotzke et al. demonstrated that a chemical inhibitor of Sec61, mycolactone, does not seem to influence antigen dislocation from the cytosol ( 85 ). This inhibitor has been shown to directly bind Sec61 and targets proteins that are co-translationally imported in a Sec61-mediated fashion into the ER toward proteasomal degradation ( 86 , 87 ). However, whether mycolactone could possibly affect Sec61-mediated protein dislocation from the ER into the cytosol is not clear, especially since such proteins are generally ubiquitinated and targeted for proteasomal degradation also in the absence of mycolactone ( 80 ). Indeed, mycolactone was shown to have no influence on ERAD ( 86 ) and also Grotzke et al. demonstrated that mycolactone does not affect protein retranslocation from the ER into the cytosol. Whether this is due to a missing role of Sec61 in this process or to specific properties of the inhibitor needs to be determined. Especially since addition of Exotoxin A, an inhibitor that blocks Sec61 channel openings ( 78 , 88 ), clearly affects antigen translocation and cross-presentation ( 49 , 82 ), there seems to be a need of information on the exact working mechanism of these inhibitors and on the role of Sec61 in dislocation from the ER to finally clear a potential role of Sec61 on cross-presentation.

In addition to antigen dislocation through a pore complex, a recent study postulated that lipid peroxidation in DCs might play a crucial role in antigen transport into the cytoplasm ( 89 ). Here, the authors proposed that the specific recruitment of NOX2 might cause lipid peroxidation in endosomes. As mentioned above, NOX2 captures protons to generate hydrogen peroxide, preventing rapid acidification of the endosome. Lipid peroxidation caused by such hydrogen peroxide was suggested to result in leakiness of the endosomal membrane and hence, antigen access into the cytosol and enhanced cross-presentation. However, it remains unclear how the antigen-presenting cell in this case would prevent inflammasome-induced cell death caused by unspecific release of cathepsins. Additionally, the necessity for endosomal antigens to be unfolded ( 76 ) and reduced by GILT ( 77 ) cannot be explained by simple leackage of the endosomal membrane. Therefore, the significance of such a pathway in cross-presentation in vivo remains to be elucidated.

Transport of Proteasome-Derived Peptides for Loading Onto MHC I

After being transported into the cytosol, internalized antigens are degraded by the proteasome. Subsequently, antigen-derived peptides can be transported through the TAP transporter into the ER or alternatively, by endosomal TAP, back into the endosomal compartments ( 44 , 45 , 47 , 48 , 90 ). There, peptides are trimmed into a suited size for loading onto MHC I molecules. Such trimming can occur via the peptidases ERAP (in the ER) or IRAP (in endosomes) (Figure 1 ) ( 91 ). Presentation of peptides derived from soluble antigens is mainly ERAP-independent in vitro and in vivo ( 92 ), but rather occurs in endosomes after transport by endosomal TAP and IRAP-mediated peptide trimming ( 90 , 92 ). Proteasome-derived peptides derived from particulate antigens, however, can be transferred into both the ER and endosomes, where they are trimmed by ERAP or IRAP, respectively, and loaded onto MHC I ( 91 ). These underlying mechanisms for these differences are unknown.

Recently, it was demonstrated that, in addition to antigen translocation through endosomal TAP, some peptides might enter endosomes in an energy-consuming but TAP-independent fashion ( 93 ), pointing out the possibility of additional (unknown) transporters involved in peptide transport into endosomes for cross-presentation. Additionally, since TAP-independency was often used to demonstrate cross-presentation via the vacuolar pathway, there is the possibility that at least in part of these studies, antigens might have entered the endosome via the endosome-to-cytosol pathway, using alternative peptide transporters.

After peptide reimport into the endosomes, they can be loaded onto MHC I molecules. In general, there are two basic possibilities how MHC I molecules can enter the endosome. First, newly synthesized MHC I molecules could be transported from the ER to the endosomes and used for peptide loading in cross-presentation. Second, MHC I from the cell surface (that are already loaded with peptides) could be transported toward endosomes during endocytosis events. The Blander group demonstrated that for particulate antigens, MHC I molecules used for cross-presentation mainly originated from the cell membrane and were translocated into an endosomal recycling compartment in a Rab11a-dependent fashion (Figure 1 ) ( 94 ). From these organelles, MHC I molecules can be transported toward phagosomes, a process that is mediated by the SNARE protein SNAP23 and critically depends on MyD88 signaling ( 94 ). It remains unclear, however, whether peptide exchange on recycling MHC I molecules requires the help of additional chaperon proteins (similar to the function of HLA-DM in MHC II-restricted presentation) or can occur after simple weakening of the peptide–MHC I binding in endosomes. Additionally, it has been demonstrated that for cross-presentation of elongated peptides, a substantial part of the used MHC I molecules are newly synthesized molecules recruited from the ER ( 95 ). In this case, it needs to be determined whether such MHC I molecules are loaded with peptides in the ER and undergo peptide exchange in acidic endosomes, or whether the transport of the entire peptide loading complex, which stabilizes unbound MHC I molecules and assists in peptide binding, to the endosomes is required for cross-presentation. Despite the presence of several members of the peptide loading machinery in endosomes ( 45 , 47 , 48 ), a functional relevance of these proteins in cross-presentation is missing.

Transport of ER Components to Endosomes

As described above, efficient cross-presentation requires the transport of ER proteins toward endosomes. The exact mechanisms, by which this transfer occurs, are not completely understood and in part contradictory data complicate a clear view on this process.

Since it is known that endosomes during their maturation directly interact with the ER to exchange a wide variety of molecules ( 96 ), such ER-endosome membrane contact sites would offer an easy explanation for the transfer of ER proteins toward endosomes. However, it has been proposed by Amigorena and Savina that the transport of cross-presentation components toward endosomes takes place from the ER-golgi intermediate compartment (ERGIC) ( 97 ). Membrane fusion between the ERGIC and the phagosomes has been postulated to be mediated by the SNARE proteins Sec22b (in the ERGIC) and syntaxin 4 (in the phagosome). Accordingly, shRNA-mediated downregulation of Sec22b resulted in impaired recruitment of ER proteins toward phagosomes, decreased antigen translocation into the cytosol, and hence reduced cross-presentation ( 94 , 97 ). These observations support a critical role of the ERAD machinery in antigen dislocation into the cytosol for cross-presentation as described above. However, a recent study by Reddy and colleagues demonstrated that severe off target effects of the used shRNA might have caused the observed influence on cross-presentation ( 98 ), questioning the role of Sec22b in cross-presentation. Since such off target effects of shRNA molecules can be circumvented by the generation of Sec22b-deficient mice, one could expect that the use of conditional knockout mice would shed light on the situation and would clearly indicate whether Sec22b is indeed involved in cross-presentation. Mice bearing a conditional knockout of Sec22b in CD11c + DCs were generated by both the Reddy and the Amigorena group. Strikingly, whereas Reddy et al. reported complete independency of cross-presentation on Sec22b ( 98 ), Amigorena et al. showed a clear impairment of cross-presentation in Sec22b-knockout DCs, hence drawing completely opposite conclusions ( 99 ). Both groups used partially different in vitro and in vivo systems to substantiate their findings, but since also opposite effects of Sec22b on cross-presentation using the same cells (BM-DCs and splenic DCs) and the same antigens (soluble and bead-bound OVA) were observed, these contractionary results cannot be explained by different experimental setups only ( 100 ). Therefore, the exact role of Sec22b and ERGIC-mediated transport of ER proteins needs to be confirmed.

The recruitment of MHC I molecules toward antigen-containing phagosomes was shown to be induced by TLR ligands. TLR-induced and MyD88-dependent signaling resulted in the activation of IKK2, which phosphorylates SNAP23, mediating fusion events between phagosomes and MHC I-containing recycling endosomes ( 94 ). Also the transport of other ER proteins toward endosomes has been shown to be stimulated by TLR ligands ( 82 , 90 ). Using flow cytometric analysis of individual endosomes ( 101 ), have demonstrated before that low amounts of Sec61 are present in endosomes also in the absence of TLR ligands, and that a clear recruitment of Sec61 toward antigen-containing endosomes was induced by LPS ( 82 ). Since it is very unlikely that Sec61 is also recruited via recycling endosomes, distinct mechanisms might come into play for the transport of these molecules.

One of these mechanisms might rely on the uncoordinated 93 homolog B1 (UNC93B1), which is activated by TLR triggering and mediates the transport of TLRs from the ER toward endosomes ( 102 – 104 ). Interestingly, UNC91B1 has been demonstrated to be critically involved in cross-presentation ( 105 ). Although a putative role of UNC93B has also been discussed controversially ( 106 ), it now becomes clear that an essential role of UNC93B1 in cross-presentation is based on its interaction with the store-operated-Ca 2+ -entry regulator STIM1. UNC93B1 has been shown to be essential for oligomerization of hence activation of STIM1, which in turn alters local Calcium signaling regulating phago/endosome fusion events ( 107 , 108 ). Ablation of UNC93B1 impairs antigen translocation into the cytosol and cross-presentation ( 107 ). Interestingly, antigen dislocation into the cytosol was impaired despite reduced endosomal antigen degradation, which is generally assumed to increase antigen export from the endosomes. Since UNC93B1 upon TLR stimulation mediates TLR transport from the ER toward endosomes, it, therefore, is thinkable that ER members of the cross-presentation machinery are transported from the ER toward endosomes in a similar UNC93B1-dependent fashion.

Additionally, DC activation by TLR ligands can have other effects on the cross-presentation machinery independent of ER to endosome transport, like the prevention of phagosome fusion with lysosomes and concomitant antigen stabilization ( 57 ) or increases in antigen internalization ( 109 ).

Alternative Cross-Presentation Pathways

In all cross-presentation pathways described above, cross-presented antigens entered the DC via endocytosis. However, there are some reports indicating that also distinct mechanisms can lead to cross-presentation.

One of these mechanisms is the transport of pre-processed antigens (peptides) from a donor cell to a DC. Such transport can occur via direct cell–cell contact, mediated by gap junctions ( 110 , 111 ). After gap junction-mediated transport from one cell to another, antigen-derived peptides can enter the normal MHC I presentation pathway. Interestingly, the donor cell does not need to be an antigen-presenting cell, offering the possibility that DCs can obtain such peptides directly from infected cells. Infection of melanoma cells with Salmonella has been demonstrated to increase the expression of Connexin 43, an important gap junction protein, enabling efficient gap junction-mediated peptide transfer from the infected cell to the DC and hence efficient cross-presentation ( 112 ). However, given the limited stability of intracellular peptides ( 113 ), the physiological significance of such peptide transfer in cross-presentation remains unclear.

Another alternative cross-presentation pathway is termed cross-dressing, which generally implies that the cross-presenting DC becomes an MHC I molecule, which has already been loaded with an antigen-derived peptide, transferred from a donor cell ( 114 , 115 ). Similar to gap junction-mediated peptide transfer, such donor cell does not necessarily need to be an antigen-presenting cell, suggesting that DCs can derive peptide-loaded MHC I molecules directly from infected cells or even apoptotic cells. The transfer of loaded MHC I molecules is thought to be mediated by cell–cell contact rather than secretory vesicles ( 114 , 116 ) and overcomes the need of intracellular antigen processing within the DC. Cross-dressing has been shown to occur in vivo ( 114 , 116 ) and cross-dressed DCs have been shown to activate memory T cells after viral infection ( 116 ). Remarkably, in this study, the activation of naive T cells did not depend on cross-dressing ( 116 ), offering the possibility that different cross-presentation pathways might be responsible for the activation of different T cell populations or for T cell activation under specific conditions. However, the exact physiological relevance of cross-dressing and especially its contribution compared to the other cross-presentation pathways in specific situations, however, remains to be elucidated.

Despite intensive research over the last decades, several questions regarding the molecular mechanisms of cross-presentation remain unsolved. How are antigens translocated into the cytosol? How are ER components recruited toward endosomes? What is the role of Sec22b and TLR ligands in this process? And probably most important: which of all these proposed mechanisms holds true in vivo ? Are different cross-presentation pathways used in vivo by distinct cell types or antigens (e.g., particulate vs. soluble), or under different physiological conditions? Without any doubt, the elucidation of the molecular mechanisms underlying cross-presentation in vivo bears a high intrinsic potential to optimize various vaccination strategies. Therefore, future investigations will be required to shed more light into the exact pathways of cross-presentation and to solve remaining controversies. The publication of clearly contradicting data might suggest the need for common protocols to perform cross-presentation experiments, in particular in regard to cell culture procedures to generate the often used BM-DCs.

Author Contributions

ME and SB designed the article and wrote the manuscript.

Conflict of Interest Statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

This work was supported by the German Research Foundation consortium SFB704 project A24.

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Keywords: dendritic cells, cross-presentation, antigen processing, endosomes, antigen dislocation

Citation: Embgenbroich M and Burgdorf S (2018) Current Concepts of Antigen Cross-Presentation. Front. Immunol. 9:1643. doi: 10.3389/fimmu.2018.01643

Received: 22 May 2018; Accepted: 04 July 2018; Published: 16 July 2018

Reviewed by:

Copyright: © 2018 Embgenbroich and Burgdorf. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY) . The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

*Correspondence: Sven Burgdorf, burgdorf@uni-bonn.de

Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.

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Front Immunol

Antigen Cross-Presentation of Immune Complexes

Barbara platzer.

1 Department of Pediatrics, Division of Gastroenterology and Nutrition, Boston Children’s Hospital, Harvard Medical School, Boston, MA, USA

Madeleine Stout

Edda fiebiger.

The ability of dendritic cells (DCs) to cross-present tumor antigens has long been a focus of interest to physicians, as well as basic scientists, that aim to establish efficient cell-based cancer immune therapy. A prerequisite for exploiting this pathway for therapeutic purposes is a better understanding of the mechanisms that underlie the induction of tumor-specific cytotoxic T-lymphocyte (CTL) responses when initiated by DCs via cross-presentation. The ability of humans DC to perform cross-presentation is of utmost interest, as this cell type is a main target for cell-based immunotherapy in humans. The outcome of a cross-presentation event is guided by the nature of the antigen, the form of antigen uptake, and the subpopulation of DCs that performs presentation. Generally, CD8α + DCs are considered to be the most potent cross-presenting DCs. This paradigm, however, only applies to soluble antigens. During adaptive immune responses, immune complexes form when antibodies interact with their specific epitopes on soluble antigens. Immunoglobulin G (IgG) immune complexes target Fc-gamma receptors on DCs to shuttle exogenous antigens efficiently into the cross-presentation pathway. This receptor-mediated cross-presentation pathway is a well-described route for the induction of strong CD8 + T cell responses. IgG-mediated cross-presentation is intriguing because it permits the CD8 − DCs, which are commonly considered to be weak cross-presenters, to efficiently cross-present. Engaging multiple DC subtypes for cross-presentation might be a superior strategy to boost CTL responses in vivo . We here summarize our current understanding of how DCs use IgG-complexed antigens for the efficient induction of CTL responses. Because of its importance for human cell therapy, we also review the recent advances in the characterization of cross-presentation properties of human DC subsets.

Introduction

The mechanism of cross-presentation allows exogenous antigens to access the processing and presentation machinery of a cell so that exogenous antigenic peptides are displayed on MHC class I molecules for T cell recognition, which consequently leads to the priming of CD8 + T cell responses. As such, the cross-presentation pathway is essential for inducing cytotoxic T-lymphocyte (CTL) responses against viruses as well as intracellular bacteria, which do not infect the APC ( 1 – 4 ). Additionally, cross-presentation is thought to be crucial in mounting immune responses against tumor antigens. Indeed, cross-priming of tumor reactive cytotoxic CD8 + T cells through cell-based tumor vaccines is a major goal in cancer immunotherapy ( 5 , 6 ). Induction, the so called priming, of tumor-specific CD8 + T cells is an appealing therapeutic strategy because the generated CTLs not only mediate antigen-specific killing of the targeted tumor via cell–cell contacts, but also provide the host with long-lasting memory responses that may prevent cancer recurrence.

Dendritic cells (DCs) have been proven to be superior in routing exogenous protein antigen toward cross-presentation; however, they comprise a heterogeneous cell population, and significant differences in the cross-presentation capacity of different DC subsets have been reported ( 4 ). Importantly, cross-presentation of antigen does not result solely in the priming of CTLs but can also lead to the induction of cross-tolerance ( 7 ). The latter immunological outcome should by all means be avoided during cancer therapy. Thus, to take full advantage of the therapeutic potential of antigen cross-presentation by DCs, significant effort was made to delineate precisely how cross-presentation is initiated and regulated. By now, many mechanistic details of antigen cross-presentation have been discovered whereas others still remain enigmatic. In contrast to MHC class II-restricted antigen presentation, the default pathway for the display of exogenous antigens for immune recognition and the induction of CD4 + T cell responses, cross-presentation in vivo is thought to be controlled rather strictly by the type of DCs used as antigen-presenting cells. In this review, we summarize the current knowledge on how immune complexes facilitate antigen cross-presentation and expand the cross-presentation capacity of specific DC subsets. We also discuss the therapeutic potential of this cross-presentation pathway.

IgG Immune-Complexed Antigens Enter the Cross-Presentation Pathway through Fc Receptors

Our immune system has to respond to a variety of different forms of antigens and thus has developed an array of mechanisms to deal with antigenic diversity. Antigens can be small soluble molecules, which are taken up by fluid phase mechanisms, or larger particles, such as bacteria, which are phagocytosed. To facilitate antigen uptake and processing, DCs also use an assortment of endocytic receptors (Figure (Figure1). 1 ). Several of these endocytic receptors belong to the C-type lectin family. For example, DEC-205, the mannose receptor, and Clec9a have been shown to efficiently shuttle antigen for cross-presentation. Several recent reviews give detailed insight into the functional differences of these endocytic receptors, and they are therefore only briefly mentioned here ( 8 – 10 ). Importantly, monoclonal antibodies against these endocytic receptors have been employed to target antigen to DCs for cross-presentation, and using this strategy, encouraging anti-tumor immunity was initiated in mice ( 11 – 13 ). Thus, strong emphasis is continuously put on targeting of cross-presenting DCs to elicit anti-tumor responses, as exhibited in several ongoing clinical trials ( 11 , 14 – 16 ). A so far therapeutically less exploited but remarkably effective way for DCs to internalize antigen for cross-presentation is via Fc receptors (Figure (Figure1). 1 ). Antigens, especially under inflammatory conditions, can be found already bound to antigen-specific antibodies, and these antigen–antibody complexes (referred to as immune complexes or immune-complexed antigen) can be recognized by Fc receptors through the Fc region of the antibodies. Binding of the immune complexes typically triggers crosslinking of the Fc receptors, their internalization together with the antigen, and shuttling of the immune complexes toward antigen presentation compartments ( 17 , 18 ).

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Dendritic cells use several mechanisms of antigen uptake for cross-presentation . (A) Several receptors have been shown to efficiently shuttle exogenous antigen into the cross-presentation pathway. (B) These receptors are now employed to target DCs in vivo for cancer immunotherapy using receptor-specific antibodies coupled with antigen. (C) Immunoglobulins can bind to antigen and form immune complexes. These immune complexes can then be taken up via Fc receptors and deliver antigen for cross-presentation. Pinocytosis seems not to be an effective mechanism for routing antigen toward cross-presentation.

Before the crucial role of Fc receptors in antigen cross-presentation was identified, their value in enhancing antibody-dependent cellular cytotoxicity (ADCC) by inflammatory cells, including neutrophils and macrophages, was already recognized ( 19 ). Enhancement of T cell proliferation via antigen-specific antibodies that bind Fc receptors became evident in the mid-1980s ( 20 – 22 ). Studies using Fcγ receptor knockout mice revealed the general requirement of Fcγ receptor engagement for the effectiveness of anti-tumor immune responses in vivo . The finding that anti-tumor antibodies require the induction of CTL responses to be effective suggested early on that Fcγ receptors contribute to anti-tumor immunity in addition to mediating ADCC ( 23 ). Shortly after, it was compellingly demonstrated that endocytosis of immune complexes via Fcγ receptor allows MHC class I-restricted antigen presentation and the priming of CTLs ( 24 , 25 ). The finding that DCs use immunoglobulin G (IgG)-immune complexes to efficiently prime specific CD8 + CTL responses was shortly thereafter confirmed in vivo ( 26 ). Furthermore, it was shown that only antigen targeting to FcγR on DCs, but not antigen targeting to surface immunoglobulins on B cells, induces efficient cross-presentation, despite the fact that both targeting strategies allow these cell types to present antigen via MHC class II with equal efficiency ( 27 ).

The therapeutic potential of Fc receptor-mediated antigen uptake for anti-tumor immunotherapy became evident early on. Studies with human cells demonstrated that coating human myeloma cells with monoclonal antibodies promotes cross-presentation of myeloma-associated antigens by human DCs. The enhanced cross-presentation of tumor antigen was preventable by pretreatment of the DCs using Fcγ receptor blocking antibodies ( 28 ). Notably, this study did not observe that Fcγ receptor-mediated antigen uptake induces significant phenotypic maturation of human DCs, as it has been described for murine DCs ( 24 , 26 , 27 ). The possible absence of maturation induction in human DCs through immune complexes is important to keep in mind with regard to a clinical applicability of Fc receptor targeting. DC maturation in the context of antigen uptake is considered to be a crucial attribute that must be achieved to induce efficient CTL responses by cross-presentation receptors because otherwise cross-tolerance may be induced ( 7 ). Overall, although there is substantial evidence suggesting that cross-presentation of immune-complexed antigen via Fcγ receptors is a promising tool to develop DC-based vaccination strategies, there are several factors, which we will discuss below, that have so far hampered the applicability.

Cross-Presentation of Immune Complexes and the Diversity of Fc Receptors

A major difficulty for studying and determining the therapeutic applicability of cross-presentation of immune complexes is the complexity of the Fcγ receptor family [Table [Table1; 1 ; Ref. ( 29 )]. Several types of Fc receptors have been found in addition to species-dependent differences. In mice, four different classes of Fcγ receptors comprising FcγRI, FcγRIIB, FcγRIII, and FcγRIV have been described. The activating Fc receptors FcγRI, FcγRIII, and FcγRIV consist of an immunoglobulin binding α-chain and a signal transducing γ-chain, which carries an immunoreceptor tyrosine-based activation motif (ITAM). In contrast, FcγRIIB is a single chain inhibitory receptor with an immunoreceptor tyrosine-based inhibitory motif (ITIM). The human FcγR system seems to be far more complex as exemplified by the presence of gene families for FcγRI and FcγRII, as well as the presence of several allelic forms for FcγRIIIA, FcγRIIIB, and FcγRIIB. Mouse FcγRIV is most closely related to human FcγRIIIA whereas mouse FcγRIII is most similar to human FcγRIIA. FcγRIIIB is unique for the human system, but both species have the inhibitory function of FcγRIIB in common.

Overview of human and murine Fcγ receptors .

Dendritic cells simultaneously express activating and inhibitory Fc receptors [reviewed in Ref. ( 18 )]. The conserved expression of an inhibitory Fc receptor along with activating Fc receptors among species suggests that Fc receptor-mediated cross-presentation is tightly regulated in vivo . The requirement of strictly controlling Fc receptor-mediated cross-presentation was demonstrated by studies that show that antibody-mediated cross-presentation of self-antigens contributes to autoimmune disease ( 34 , 35 ). The authors looked at the development of autoimmune diabetes in RIP-OVA mice. In this model, the transfer of OVA-specific naïve CD8 + T cells induces peripheral tolerance. Importantly, the co-administration of anti-OVA IgG leads to CD8 + T cell-driven diabetes through the activating Fcγ receptors on DCs. The disease pathogenesis in this model was further augmented in FcγRIIB knockout mice, suggesting a tolerogenic function of FcγRIIB in vivo . In line with a tolerogenic function of this receptor, it was shown that DCs from FcγRIIB knockout mice generate overall stronger immune responses and that blocking immune complex binding to FcγRIIB promotes DC maturation, which is considered one of the most important factors for efficient priming of CTL responses ( 36 – 39 ). This suggests that expression of inhibitory FcγRIIB, which restricts DC maturation under non-inflammatory conditions and thus probably prevents autoimmunity, may hamper immunotherapeutic approaches against tumors and microbial infections ( 29 , 40 ). Hence, it is important to be aware of the expression patterns and ratios of activating versus inhibitory Fc receptors on murine and human DCs when studying the effects of immune complexes.

Additionally, IgG subclass composition of immune complexes has been shown to influence binding affinity resulting in different binding properties to individual Fc receptors ( 41 ). For example, immune complexes composed of human IgG1 bind with relatively high affinities to all Fc receptors, whereas IgG2 immune complexes seem to bind primarily to human FcγRIIA and FcγRIIIA ( 42 ). Furthermore, disparities in the binding affinities of immunoglobulin isotypes for specific Fcγ receptors exist between mice and humans. Thus, predictions of immune complex functions drawn from wild-type mouse models might be inadequate. A prominent example of the failure of previous studies in accurately recapitulating the specificity and diversity of Fcγ receptor interactions is the outcome of a clinical trial using a CD28-specific superagonistic antibody; this led to severe side effects including severe pain and extreme swelling, as well as one individual suffering from heart, liver, and kidney failure ( 43 ). To address this problem, an FcγR humanized mouse strain was recently generated through transgenic expression of the entire human FcγR family under the control of their human regulatory elements on a genetic background lacking all mouse FcγRs ( 44 ). The animals demonstrate normal lymphoid tissue development and generate normal immune responses. Thus, this mouse strain offers a greatly improved model to study immune complex-mediated cross-presentation, although it addresses only the species-specific differences regarding Fcγ receptors. Humans and mice also display differences in the expression patterns of Fc receptors for IgE and IgA, which might contribute to cross-presentation of immune-complexed antigen in vivo ( 45 – 48 ).

Increasing evidence suggests that allelic isoforms and polymorphisms of Fc receptors are shaping immune responses in humans. FcγRIIA (CD32A), the major phagocytic FcγR in humans, exhibits a polymorphism in the ligand-binding domain ( 49 ). Individuals homozygous for the R allelic form of CD32A (CD32AR allele) have been described as more susceptible to bacterial infections and autoimmune diseases compared to individuals homozygous for the H allelic form of CD32A (CD32AH) and CD32AR/H heterozygous individuals ( 50 , 51 ). A binding study using two-dimensional affinity measurements also demonstrated that compared to CD32AH, CD32AR has significantly lower affinity toward IgG2, as well as to IgG1 and IgG3, suggesting that the lower binding of CD32AR to IgGs might be responsible for the lack of immune complex clearance, which leads to increased susceptibility to bacterial infections and autoimmune diseases ( 52 ). Genetic variations in Fc receptors have also been linked to cancer susceptibility ( 53 – 55 ). However, less efficient immune complex binding might also be reflected in less efficient antigen uptake and presentation via this receptor, and thus consequences for immune complexes cross-presentation should be expected. Of note, glycosylations in the IgG–Fc region can also affect Fc receptor-binding properties as discussed in detail in a recent review ( 56 ). How antigen cross-presentation of immune complexes and T cell priming is altered by differences in IgG subclass composition, IgG–Fc glycosylation, and Fc receptor polymorphisms is currently unknown, but is important to address. In conclusion, the complexity of interactions of IgG with the Fc receptor system in addition to concerns about species specificity presents a major hurdle that needs to be overcome for successful therapeutic applications.

Cross-Presentation of Immune Complexes and the Diversity of DC Subpopulations

Whether it would be beneficial to target a specific DC subset that displays a superior capacity to cross-present antigen for therapeutic approaches is currently a field of extensive investigation ( 4 , 57 ). We will first focus on what we know so far about the cross-presentation capacity of DC subsets in general and then discuss our current understanding of cross-presentation of immune complexes in regard to DC subsets. DCs are a heterogeneous cell population, and substantial effort was made to characterize different subsets in mice and identify their human counterparts [reviewed in Ref. ( 58 – 60 )]. In principal, murine and human DCs can be divided into two major subsets, classical/conventional DCs (cDCs) and plasmacytoid DCs (pDCs). In mice, cDCs comprise CD8α + and CD8α − lineages, which have been found to differ in their ontogeny and display functional specializations. Since the expression of surface markers on human and murine DCs is not conserved, only recently has gene expression profiling allowed for the identification of human CD141 + DCs as functional equivalents of the mouse CD8α + DCs, while human CD1c + DCs appear to be comparable to mouse CD8 - DCs ( 61 , 62 ).

In mice, the CD8α + DC subset is considered to be more efficient at antigen cross-presentation than other DC subsets ( 63 – 66 ). The corresponding human subset, CD141 + DCs, is also potent at inducing CD8 + T cell responses in vitro , although their superiority to other human DC subsets is uncertain ( 67 – 73 ). Several groups have now reported that all human DC subsets can efficiently cross-present several forms of antigen [reviewed by Ref. ( 57 )]. Initially, CD141 + DCs isolated from human blood were described to better cross-present CMV protein pp65 in comparison to CD1c + DCs and pDCs from the same donor ( 67 ). It is important to note, however, that cross-presentation in vivo occurs rather in secondary lymphoid organs. A recent study has overcome the difficulties in isolating sufficient amounts of human DCs from lymphoid tissue and characterized in detail the cross-presentation properties of tonsil-resident DCs ( 73 ). An important finding of this study was that all tonsillar DC subsets (i.e., pDCs and the two populations of cDCs, CD1c + DCs and CD141 + DCs) displayed comparable capacities to cross-present soluble antigens in contrast to macrophages, which lacked this ability. Interestingly, necrotic cells were phagocytosed and cross-presented by CD1c + DCs and CD141 + DCs with similar efficiency, while pDCs were poor at taking up necrotic particles, consequently resulting in inefficient cross-presentation. Tonsillar macrophages were found to be the most efficient at taking up dead cells, but despite this fact they completely failed to cross-present necrotic cells. Collectively, the ability to efficiently cross-present in humans seems less restricted to a specific DC subpopulation than as observed in mice. Along these lines, it has been shown that the cross-presentation properties of human DCs depend on the antigen uptake pathway and the ability of the pathway to route the antigen into an early endosomal compartment rather than on a specific DC subset ( 74 , 75 ). CD141 + DCs are superior cross-presenters compared to CD1c + DCs only when the antigen is delivered via CD205, a receptor that preferentially targets antigens to late endo/lysosomal compartments. If antigen is targeted through CD40, CD1c + DCs are as efficient as CD141 + DCs. These findings argue that targeting one specific DC subset for the design of DC-based vaccines may not offer the presumed advantage.

The cross-presentation studies discussed above focused primarily on soluble antigen uptake and targeting antigen via several endocytic receptors. How does cross-presentation of immune complexes fit into this picture? Targeting DCs through IgG immune complexes has been proven to be superior to soluble immune complexes for inducing CD8 + T cell responses and as anti-tumor vaccines by utilizing murine bone marrow-derived DCs ( 76 , 77 ). In addition, circulating specific antibodies have been shown to enhance systemic cross-priming by delivering immune-complexed antigen to murine DCs in vivo ( 78 ). Notably in mice, immune-complexed antigen allows the CD8α − DC subset, which has been proven to be very poor at presenting soluble antigen, to become potent cross-presenting cells ( 79 ). Interestingly, cross-presentation by CD8α − DCs depends on activating Fcγ receptors. Lack of the signal transducing γ-chain specifically abolishes presentation of immune-complexed antigen on MHC class I molecules but not on MHC class II molecules ( 79 ). Another remarkable feature regarding cross-presentation of immune complexes is their reliance on FcRn, an IgG binding receptor that is primarily located intracellularly and binds IgG independently from their Fcγ receptor interaction sites ( 80 ). How FcRn promotes cross-presentation of immune complex is discussed later in more detail.

Our knowledge regarding cross-presentation of immune-complexed antigen by human DC subsets is still very limited. The effects of Fcγ receptor antigen targeting on the efficiency of cross-presentation in human DCs were recently investigated using human cytomegalovirus (HCMV) pp65 as a protein antigen ( 81 ). In line with the data obtained from murine models, immune-complexed antigen is more efficiently cross-presented than comparable amounts of soluble antigen by human DCs. The enhanced cross-presentation capacity observed was not mediated by increased antigen uptake or induction of DC maturation through the immune-complexed antigen. The authors also demonstrated that both of the two major intracellular cross-presentation pathways ( 4 ), the cytosolic and the vacuolar/endosomal pathway, are involved in Fcγ receptor-mediated uptake of immune complexes and their processing. Notably, monocyte-derived DCs as well as CD141 + DCs required antigen processing by both intracellular pathways. The finding that CD141 + DCs, which are the human equivalent to CD8α + DCs, use both processing pathways for immune complexes points to unique features of human DCs. Murine CD8α + DCs mainly use the cytosolic pathway to process antigen for cross-presentation, including the processing of immune complexes ( 82 ). Another difference to murine DCs is that the CD141 + DC subset proved to be superior to CD1c + DCs in cross-presenting pp65 immune complexes ( 81 ). These findings point to obvious differences between murine and human DC subsets regarding immune complex-mediated cross-presentation. Since the human DCs were isolated from blood ( 81 ) and the murine DCs were isolated from the spleen ( 79 , 80 ), it is possible that DCs from blood and lymphoid tissue generally differ in their cross-presentation capacities of immune complexes, which have similarly been observed for human DC subsets in response to soluble antigen as described above. In any case, the study by Flinsenberg et al. found that Fcγ receptor targeting increases cross-presentation of HCMV antigen by human blood and tonsillar CD141 + DCs, which suggest that targeting of this DC subset with immune complexes might improve DC-based vaccination strategies. Another very important aspect of this study is the detailed characterization of Fcγ receptor expression on human DC subsets. Although CD1c + DCs expressed overall higher levels of FcγRII, CD141 + DCs seem to express higher levels of the activating FcγRIIA relative to the inhibitory FcγRIIB. Thus, this study clearly demonstrates that the overall expression level of one specific Fcγ receptor does not determine the functional outcome, and that we need to consider the diversity of Fcγ receptor expression by distinct DC subsets to evaluate the therapeutic potential of immune complex-mediated cross-presentation.

A further difference between mice and humans seems to be the cross-presentation capacity of pDCs. Several studies have reported that murine pDCs do not possess the ability to cross-present ( 83 – 86 ) or that their capacity is insignificant when compared to cDCs ( 87 ). In contrast to mouse pDCs, human pDCs can efficiently cross-present antigen and induce CD8 + T cell responses ( 88 – 90 ). Human pDCs also express FcγRIIA, and this receptor has been shown to mediate internalization of immunoglobulins bound to chromatin ( 91 ), Coxsackie virus ( 92 ), the model antigen KLH ( 93 ), and the tumor antigen NY-ESO-1 ( 94 ). In addition, the group of de Vries described that pDCs can use several receptor-targeted antigen uptake pathways, including the activating FcγRIIA receptor, to target antibody-coated nanoparticles for cross-presentation. Although this study did not use classical immune complexes, together with a vaccination study in which pDCs significantly prolonged overall survival in melanoma patients ( 95 ), it supports the notion that pDCs are interesting targets for DC-based immunotherapeutic strategies.

Collectively, we should keep in mind that some of the observed differences between human and murine DC subsets regarding cross-presentation of immune complexes most likely stem from differences in their Fc receptor expression and from different binding affinities for IgG isotypes. Recently, various published and publicly available microarray data were compiled, and this mRNA collection provides an excellent overview of mouse and human Fcγ receptor expression by DC subsets, monocytes, and macrophages ( 18 ). Overall, the Fcγ receptor expression levels obtained by mRNA analysis correspond well with the surface expression levels acquired by flow cytometric analysis (FACS) (Table (Table2). 2 ). For the future, it will be important to determine whether the Fcγ receptor expression of human DC subsets isolated from blood also matches the expression on tissue-resident DCs from different organs.

Fcγ receptor expression by murine and human DC subsets .

a Published surface expression determined by flow cytometric analysis (FACS) ( 81 , 96 – 98 ) .

b mRNA data from compiled microarrays ( 18 ) .

c CD1c + DCs isolated from blood; tonsillar CD1c + : DC −/+ .

nd: not determined .

na: not applicable .

Regulation of Fcγ Receptor Expression Impacts Cross-Presentation of Immune Complexes

Efficient cross-presentation for inducing protective immune responses against tumors or viruses is strongly governed by the ratio of activating versus inhibitory Fcγ receptors expressed on DCs. In addition to the DC subset, the maturation/activation state of DCs likely impacts their Fcγ receptors expression pattern. The maturation/activation state of DCs is in general strongly influenced by the cytokine milieu of the microenvironment, and a considerable number of cytokines have been shown to regulate Fcγ receptor expression in vitro . TGF-β1 down-regulates surface expression FcγRI and FcγRIII on monocytes ( 99 ). IL-4, a cytokine associated with Th2-type immune responses, increases the expression of inhibitory FcγRIIB. In contrast, the Th1-cytokine IFN-γ increases expression of activating Fc receptors on monocytes ( 100 ). Monocytes also have been shown to respond to IFN-γ and TNF-α treatment with enhanced immune complex binding via FcγRI, even when saturated with pre-bound monomeric IgG ( 101 ). Cytokine-induced changes in Fcγ receptor expression were also found using monocyte-derived DCs ( 96 ). Immature DCs generated with GM-CSF and IL-4 from monocytes express high amounts of inhibitory FcγRIIB, which is down-regulated upon DC maturation induced by TNF-α. The authors also showed that blood DCs activated with a cytokine cocktail containing TNF-α, IL-1β, IL-6, and PGE2 induce more influenza-specific CD8 + T memory cells via targeting of FcγRI and FcγRIIA. Interestingly, crosslinking of inhibitory FcγRIIB only reduced the cross-presentation ability of immature DCs but not of mature DCs. Treatment of mature blood DCs with IL-10, or a combination of IL-10 and IL13, was found to increase expression of FcγRIIA and FcγRIIB ( 96 ). To sum up, although we know that cytokines can modulate Fcγ receptor expression, and that tumors create cytokine-rich microenvironments that involve the production of immunosuppressive as well as inflammatory cytokines to drive tumor progression ( 102 , 103 ), our knowledge is very limited as to how cytokines from the tumor microenvironment affect cross-presentation of immune complexes by DCs. Thus, regarding anti-tumor therapy, this gap in knowledge might explain why the long-term therapeutic outcomes of immune complex-based strategies were not more successful, although efficient cross-presentation is induced by IgG-complexed antigens. One explanation could be that the tumor microenvironment promotes the induction of cross-tolerance by keeping the DCs in an immature state, which is associated with high expression levels of inhibitory FcγRIIB. Another possible scenario would be that immune complex-mediated cross-presentation via activating Fcγ receptors, which is known to result in inflammatory cytokine production by the DCs, actually contributes to an inflammatory tumor microenvironment, which fosters tumor progression by supporting, for example, angiogenesis. Therefore, future studies are needed that not only address which activating and inhibitory Fcγ receptors are expressed by DC subsets, but also define how their expression patterns are regulated and which cytokines are induced by DC subsets after immune complex-mediated activation in vivo .

FcRn – An Intracellular Relay Receptor That Guides Cross-Presentation of IgG-Containing Immune Complexes

In general, little is known about the intracellular mechanisms that are involved in processing of immune-complexed antigen for cross-presentation. Substantial evidence exists for an important role of FcRn in the cross-presentation of IgG-containing immune complexes. FcRn, which is an MHC class I-like molecule, was initially described only in intestinal epithelial cells of neonatal rodents, but it has since been shown to be expressed throughout life in several cell types, including human and rodent DCs ( 104 – 106 ). If CD8α − DCs do not express FcRn because of genetic alterations, the cell loses its ability to efficiently cross-present and fails to elicit CD8 + T cell responses ( 80 ). Elegant studies showed that FcRn regulates the intracellular sorting of IgG immune complexes in CD8α − DCs. In contrast to CD8α + DCs where the endosomes are buffered around the neutral pH of 7.0 that prevents antigen degradation and promotes cross-presentation, Fcγ receptors in CD8α − DCs traffic antigens into acidic compartments (pH 6.0). The acidic environment is, by itself, not favorable for cross-presentation; however, it favors the binding of IgG to FcRn, and thus the model proposes that FcRn traps immune-complexed antigen and protects it from degradation within an acidic loading compartment. The study also showed that in parallel to antigen entry into the FcRn-positive compartment, key components of the phagosome-to-cytosol cross-presentation machinery are rapidly recruited to the endo/lysosome. Vesicles that contained IgG-opsonized particles or IgG immune complexes rapidly acquired greater quantities of vacuolar ATPase (V-ATPase), gp91phox, and Rab27a than those that resulted from internalization of IgG mutants that cannot interact with FcRn. Consistent with this concept, it was described that the presence of FcRn also affects the oxidation state as well as the acidification of vesicles. Inhibitor studies demonstrated that FcRn-mediated cross-presentation depends on the proteasome as well as Sec61α, which is indicative for the cytosolic cross-presentation pathway. Since insulin-regulated amino peptidase (IRAP) enrichment was not depicted in FcRn-positive IgG immune complex-containing vesicles, and cathepsin inhibitors did not abrogate IgG immune complex cross-presentation, the authors concluded that the alternative vacuolar pathway was not involved. In summary, this study suggests that FcRn binding of IgG immune complexes enables a slower and more controlled antigenic degradation in CD8α − DCs, thereby permitting this population of DCs to become efficient cross-presenting cells.

The most compelling evidence for the exceptional importance of FcRn for cross-presentation of IgG immune complexes and IgG-opsonized particles is derived from in vivo studies that analyzed the effects of FcRn-deficiency on chronic intestinal inflammation and colonic cancer ( 107 , 108 ). In a chemically induced chronic colitis model, which is associated with generating high levels of anti-bacterial antibodies that enter the host as IgG immune complexes, Baker et al. demonstrated that FcRn-dependent cross-presentation is carried out by CD8α − DCs in vivo , leading to greater levels of cytotoxic T cell activation during the course of colitis. In a recent study, the same group focused on the impact of FcRn on tumor development, clearly demonstrating the importance of this molecule for anti-tumor immune surveillance ( 108 ). The authors found that the DC-specific deletion of FcRn leads to increased tumor burden in experimental models of colon cancer and lung metastasis. Strikingly, this study also demonstrated that colon cancer patients with higher numbers of FcRn-positive DCs in the adjacent tumor tissue had significantly better prognoses, confirming the crucial role of FcRn and demonstrating the vital role of cross-presentation of IgG immune complexes in anti-tumor immunity in general. It will now be of utmost importance to elucidate the details of the intracellular mechanism of this process to evaluate whether the pathway can be employed for cancer immunotherapy.

Although ample evidence suggests that Fcγ receptor targeting through immune complexes allows for more efficient cross-presentation compared to soluble antigen, it still needs to be proven which advantages it may have over targeting of other endocytic receptors on DCs, especially in vivo . In this respect, it is very important to continue developing better murine models which more accurately reflect the human immune system. The recently published humanized FcγR mouse strain is here a promising step in the right direction. For therapeutic manipulations, we also need to better understand how Fcγ receptor expression by DCs is regulated. Can we use cytokines and/or TLR ligands to modulate the ratio of inhibitory versus activating Fcγ receptors expressed by DC subsets to improve therapeutic strategies? TLR-2 ligands, for example, have been shown to increase expression of inhibitory FcγRIIB in macrophages ( 109 ), a consequence not desirable in the context of viral or tumor vaccine development. Furthermore, how does the size of immune complexes influence cross-presentation? How does the antibody to antigen ratio in immune complexes influence cross-presentation? Indeed, it has been shown that immune complex size and glycosylation on IgG impact the binding to human Fcγ receptors ( 110 ). In summary, it is fair to conclude that many important questions remain open and need to be addressed. Irrespectively, cross-presentation of immune complexes represents an exciting potential pathway to improve DC-based vaccination strategies for anti-viral as well as anti-tumor therapy.

Conflict of Interest Statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Acknowledgments

This work was supported by grants from the National Institutes of Health: K01DK093597 (to Barbara Platzer) and AI075037 (to Edda Fiebiger). This work was also supported by the Harvard Digestive Diseases Center Grant P30DK034854.

The show and tell of cross-presentation

Affiliations.

1 Jill Roberts Institute for Research in Inflammatory Bowel Disease, Weill Cornell Medicine, Cornell University, New York, NY, United States; Joan and Sanford I. Weill Department of Medicine, Weill Cornell Medicine, Cornell University, New York, NY, United States; Department of Microbiology and Immunology, Weill Cornell Medicine, Cornell University, New York, NY, United States; Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, Cornell University, New York, NY, United States; Immunology and Microbial Pathogenesis Programs, Weill Cornell Graduate School of Medical Sciences, Weill Cornell Medicine, Cornell University, New York, NY, United States. Electronic address: [email protected].
2 Jill Roberts Institute for Research in Inflammatory Bowel Disease, Weill Cornell Medicine, Cornell University, New York, NY, United States; Joan and Sanford I. Weill Department of Medicine, Weill Cornell Medicine, Cornell University, New York, NY, United States.
PMID: 37996207
DOI: 10.1016/bs.ai.2023.08.002

Cross-presentation is the culmination of complex subcellular processes that allow the processing of exogenous proteins and the presentation of resultant peptides on major histocompatibility class I (MHC-I) molecules to CD8 T cells. Dendritic cells (DCs) are a cell type that uniquely specializes in cross-presentation, mainly in the context of viral or non-viral infection and cancer. DCs have an extensive network of endovesicular pathways that orchestrate the biogenesis of an ideal cross-presentation compartment where processed antigen, MHC-I molecules, and the MHC-I peptide loading machinery all meet. As a central conveyor of information to CD8 T cells, cross-presentation allows cross-priming of T cells which carry out robust adaptive immune responses for tumor and viral clearance. Cross-presentation can be canonical or noncanonical depending on the functional status of the transporter associated with antigen processing (TAP), which in turn influences the vesicular route of MHC-I delivery to internalized antigen and the cross-presented repertoire of peptides. Because TAP is a central node in MHC-I presentation, it is targeted by immune evasive viruses and cancers. Thus, understanding the differences between canonical and noncanonical cross-presentation may inform new therapeutic avenues against cancer and infectious disease. Defects in cross-presentation on a cellular and genetic level lead to immune-related disease progression, recurrent infection, and cancer progression. In this chapter, we review the process of cross-presentation beginning with the DC subsets that conduct cross-presentation, the signals that regulate cross-presentation, the vesicular trafficking pathways that orchestrate cross-presentation, the modes of cross-presentation, and ending with disease contexts where cross-presentation plays a role.

Keywords: Bacteria; CDC1; CDC2; Cancer; Chlamydia; Cross-presentation; Dendritic cells; Endosomal recycling compartment; Immune evasion; MHC-I; Mycobacteria; SNARE; Toll-like receptor; Transporter associated with antigen processing; Vesicular traffic; Virus.

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural
Antigen Presentation
Antigens / metabolism
CD8-Positive T-Lymphocytes
Cross-Priming*
Dendritic Cells
Histocompatibility Antigens Class I / metabolism
Membrane Transport Proteins / metabolism
Neoplasms* / metabolism
Peptides / metabolism
Histocompatibility Antigens Class I
Membrane Transport Proteins

Grants and funding

R01 AI170832/AI/NIAID NIH HHS/United States
R01 AI170897/AI/NIAID NIH HHS/United States
R21 AI159772/AI/NIAID NIH HHS/United States
T32 DK116970/DK/NIDDK NIH HHS/United States

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COMMENTS

Cross-presentation
Cross-presentation is the ability of certain professional antigen-presenting cells (mostly dendritic cells) to take up, process and present extracellular antigens with MHC class I molecules to CD8 T cells (cytotoxic T cells). Cross-priming, the result of this process, describes the stimulation of naive cytotoxic CD8 + T cells into activated cytotoxic CD8 + T cells.
Current Concepts of Antigen Cross-Presentation
The dependency of cross-presentation on proteasomal degradation seems logical, since the functional outcome of cross-presentation is the activation of antigen-specific cytotoxic T cells. After migration toward to site of infection, these T cells are fully equipped to kill potential target cells, like virus-infected cells or tumor cells.
Cross-presentation by dendritic cells
The presentation of exogenous antigens on MHC class I molecules, known as cross-presentation, is essential for the initiation of CD8+ T cell responses. In vivo, cross-presentation is mainly ...
Understanding the Biology of Antigen Cross-Presentation for the Design
Antigen cross-presentation, the process in which exogenous antigens are presented on MHC class I molecules, is crucial for the generation of effector CD8 + T cell responses. Although multiple cell types are being described to be able to cross-present antigens, in vivo this task is mainly carried out by certain subsets of dendritic cells (DCs). Aspects such as the internalization route, the ...
Cross Presentation
Cross-presentation has been traditionally broken down into two pathways focusing on where the antigen is delivered and the molecules involved in its processing: the vacuolar pathway, also known generally as a TAP-independent pathway, and the phagosome-to-cytosol pathway, which is a TAP-dependent pathway (Amigorena & Savina, 2010; Lin et al., 2008; Rock & Shen, 2005).
The evolving biology of cross-presentation
2. Origins and experimental model systems of cross-presentation. We recently reviewed the discoveries of DCs and of cross-presentation [].The original identification of DCs dates to 1973 with Steinman's report of stellate cells [], followed by several studies that established these cells as a novel immune lineage with distinct APC functions.These cells were found to be distinct from ...
Antigen cross-presentation by dendritic cells: A critical axis in
Antigen cross-presentation is a process by which DCs acquire and process exogenous antigens into peptides that are then loaded on MHC class I molecules for presentation to CD8 + T cells [104], [105] (Fig. 2).This process is essential for initiating CD8 + T cell responses against tumors and intracellular pathogens [58], [106], [107].The process of antigen cross-presentation by DCs can be ...
A Comprehensive Experimental Guide to Studying Cross‐Presentation in
Cross-presentation was first observed serendipitously in the 1970s. The importance of it was quickly realized and subsequently attracted great attention from immunologists. Since then, our knowledge of the ability of certain antigen presenting cells to internalize, process, and load exogenous antigens onto MHC-I molecules to cross-prime CD8 + T ...
Cross-Presentation
Abstract. Cross-presentation is the culmination of complex subcellular processes that allow the processing of exogenous proteins and the presentation of resultant peptides on major histocompatibility class I (MHC-I) molecules to CD8 T cells. Dendritic cells (DCs) are a cell type that uniquely specializes in cross-presentation, mainly in the ...
Cross‐presentation: underlying mechanisms and role in immune
Cross-presentation was originally discovered as an obscure phenomenon in transplantation immunity. However, it is now clear that it is a major mechanism by which the immune system monitors tissues and phagocytes for the presence of foreign antigen. Cross-presentation is the only pathway by which the immune system can detect and respond to viral ...
A guide to antigen processing and presentation
Abstract. Antigen processing and presentation are the cornerstones of adaptive immunity. B cells cannot generate high-affinity antibodies without T cell help. CD4 + T cells, which provide such ...
Cross-presentation in viral immunity and self-tolerance
Cross-presentation is defined as the processing of exogenous antigens into the major histocompatibility complex (MHC) class I pathway. Cross-priming and cross-tolerance refer to the induction of ...
Frontiers
The dependency of cross-presentation on proteasomal degradation seems logical, since the functional outcome of cross-presentation is the activation of antigen-specific cytotoxic T cells. After migration toward to site of infection, these T cells are fully equipped to kill potential target cells, like virus-infected cells or tumor cells.
Current Concepts of Antigen Cross-Presentation
Abstract. Dendritic cells have the ability to efficiently present internalized antigens on major histocompatibility complex (MHC) I molecules. This process is termed cross-presentation and is important role in the generation of an immune response against viruses and tumors, after vaccinations or in the induction of immune tolerance.
Cross-Presentation: How to Get there
Cross-presentation has been demonstrated to play an important role in a variety of processes, including the induction of an immune response against viruses that do not infect antigen-presenting cells directly or against tumors of non-hematopoietic origin (Huang et al., 1994; Sigal et al., 1999; den Haan and Bevan, 2001; Heath and Carbone, 2001).
A Comprehensive Experimental Guide to Studying Cross-Presentation in
Cross-presentation was first observed serendipitously in the 1970s. The importance of it was quickly realized and subsequently attracted great attention from immunologists. Since then, our knowledge of the ability of certain antigen presenting cells to internalize, process, and load exogenous antigens onto MHC-I molecules to cross-prime CD8 + T ...
Cross-presentation: a general mechanism for CTL immunity and tolerance
MHC class I-restricted presentation is usually associated with the processing of endogenous antigens. However, this restriction element can present antigens that do not originate within the presenting cells. Here, Francis Carbone and colleagues describe how such cross-presentation is critical for cytotoxic T-cell surveillance of peripheral antigens, both self and foreign, located outside the ...
Cross-presentation: underlying mechanisms and role in immune
Cross-presentation was originally discovered as an obscure phenomenon in transplantation immunity. However, it is now clear that it is a major mechanism by which the immune system monitors tissues and phagocytes for the presence of foreign antigen. Cross-presentation is the only pathway by which the immune system can detect and respond to viral ...
A Comprehensive Experimental Guide to Studying Cross-Presentation in
Over the years, we have extensively studied DC cross-presentation in mice. We have carefully optimized the conditions to study this process in murine cells, including the isolation and differentiation of murine DCs, the isolation of antigen-specific transgenic murine CD8 + T cells, stimulating DCs for cross-presentation with soluble or particulate cargoes, and cross-priming CD8 + T cells by DCs.
Defining cross presentation for a wider audience
Cross presentation is the process of production of peptide-MHC Class I complexes by cells in which the antigen that is the source of peptide is not translated. The majority of recent studies have described many facets of the classical TAP-dependent cross presentation pathway, but numerous pathways f …
The evolving biology of cross-presentation
Notably, one caveat of interpretations made regarding the TAP requirement for cross-presentation is the use of cells deficient in TAP. Tap1 −/− mice have reduced MHC-I surface expression and very low numbers of CD8 T cells in the thymus, spleen, blood, and LNs [133].Decreased numbers of MHC-I molecules alone might explain impaired cross-presentation seen with Tap1 −/− APCs.
Antigen Cross-Presentation of Immune Complexes
A prerequisite for exploiting this pathway for therapeutic purposes is a better understanding of the mechanisms that underlie the induction of tumor-specific cytotoxic T-lymphocyte (CTL) responses when initiated by DCs via cross-presentation. The ability of humans DC to perform cross-presentation is of utmost interest, as this cell type is a ...
The show and tell of cross-presentation
Abstract. Cross-presentation is the culmination of complex subcellular processes that allow the processing of exogenous proteins and the presentation of resultant peptides on major histocompatibility class I (MHC-I) molecules to CD8 T cells. Dendritic cells (DCs) are a cell type that uniquely specializes in cross-presentation, mainly in the ...

Cross-presentation in viral immunity and self-tolerance

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Introduction

Cross-Presenting DC Subsets

Major Pathways of Antigen Cross-Presentation

Delayed Antigen Degradation and its Role in Cross-Presentation

Antigen Translocation into the Cytosol as Critical Step in Antigen Cross-Presentation

Transport of Proteasome-Derived Peptides for Loading Onto MHC I

Transport of ER Components to Endosomes

Alternative Cross-Presentation Pathways

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Antigen Cross-Presentation of Immune Complexes

Madeleine Stout

Introduction

IgG Immune-Complexed Antigens Enter the Cross-Presentation Pathway through Fc Receptors

Cross-Presentation of Immune Complexes and the Diversity of Fc Receptors

Cross-Presentation of Immune Complexes and the Diversity of DC Subpopulations

Regulation of Fcγ Receptor Expression Impacts Cross-Presentation of Immune Complexes

FcRn – An Intracellular Relay Receptor That Guides Cross-Presentation of IgG-Containing Immune Complexes

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The show and tell of cross-presentation

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